Compounds for inhibition of proteolysis

Abstract

PCT No. PCT/US93/06593 Sec. 371 Date Feb. 13, 1995 Sec. 102(e) Date Feb. 13, 1995 PCT Filed Jul. 14, 1993 PCT Pub. No. WO94/01126 PCT Pub. Date Jan. 20, 1994This invention features compounds of the formula: W-Y-CH2-Q wherein W is a farnesyl group, a geranylgeranyl group, a substituted farnesyl group or a substituted geranylgeranyl group or a lipophilic unsaturated hydrocarbon; Y is: -S-, -O-, -Se-, (I), (II), (III), (IV), (V) or -CH2-; Q is (VI) wherein T1 is: H, F, or -(CH2)n-X1; T2 is: -NHCOCH3, -NH(CH2)n-X1, (VII) or a peptide of 20 or fewer amino acids; wherein X1 is: -SH, -COOH, or -CONH2; and n is an integer less than 20; T3 is: (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), -CH2-X2, (XV), (XVI), or -CF2-X2 wherein X2 is a peptide of 20 or fewer amino acids linked to carbon via the amino terminal nitrogen of said peptide; X3 is a peptide of 20 or fewer amino acids linked via an alpha carbon of said peptide; and n is an integer less than 20, said compound being characterized by inhibiting enzymatic proteolysis of a peptide having the carboxyl-terminal motif -CAAX wherein C=cysteine, A=aliphatic amino acid, and X=any amino acid.

I claim: 
     
       1. A compound of the formula:   W--Y--CH.sub.2 --Q     wherein   W is: a farnesyl group, a geranylgeranyl group, a substituted farnesyl group, a substituted geranylgeranyl group or a lipophilic unsaturated hydrocarbon; Y is: ##STR5## wherein T 1  is: H, F, or --(CH 2 ) n  --X 1  ;   T 2  is: --NHCOCH 3 , ##STR6## or a peptide of 20 or fewer amino acids; wherein X 1  is: --SH, --COOH, or --CONH 2  ; and n is an integer less than 20; ##STR7## wherein X 2  is a peptide of 20 or fewer amino acids linked to carbon via the amino terminal nitrogen of said peptide; X 3  is a peptide of 20 or fewer amino acids linked via an alpha carbon of said peptide; and n is an integer less than 20, said compound being characterized by inhibiting enzymatic proteolysis of a peptide having the carboxyl-terminal motif -CAAX (SEQ ID NO: 3) wherein C=cysteine, A=aliphatic amino acid, and X=any amino acid.   
     
     
       2. The compound of claim 1 wherein Y is --S--. 
     
     
       3. The compound of claim 1 wherein T 1  is H; T 2  is --NHCOCH 3 , and ##STR8## 
     
     
       4. The compound of claim 1 wherein T 1  is H; T 2  is: ##STR9## and n is an integer less than three. 
     
     
       5. The compound of claim 1 wherein T 1  is H; T 2  is --NHCOCH 3 , and T 3  is --CH 2  --X 2 . 
     
     
       6. A method for preparing a medicament for inhibiting neoplastic cell growth, said method comprising admixing the inhibitor of claim 1 with a pharmaceutically acceptable carrier. 
     
     
       7. The compound of claim 1 wherein W is farnesyl, Y is --S--, ##STR10## and X 2  is a peptide of three or fewer amino acids. 
     
     
       8. The compound of claim 1 having the formula ##STR11## wherein W is farnesyl and Y is --S--. 
     
     
       9. The compound of claim 1 having the formula ##STR12## wherein W is farnesyl and Y is --S--. 
     
     
       10. The compound of claim 1 having the formula ##STR13## wherein W is farnesyl and Y is --S--. 
     
     
       11. The compound of claim 1 having the formula ##STR14## wherein W is farnesyl and Y is --S--. 
     
     
       12. The compound of claim 1 having the formula ##STR15## wherein W is farnesyl and Y is --S--. 
     
     
       13. The compound of claim 1 having the formula ##STR16## wherein W is farnesyl and Y is --S--. 
     
     
       14. The compound of claim 1 having the formula ##STR17## wherein W is farnesyl and Y is --S--. 
     
     
       15. The compound of claim 1 having the formula ##STR18## wherein W is farnesyl and Y is --S--. 
     
     
       16. The compound of claim 1 having the formula ##STR19## wherein W is farnesyl and Y is --S--.